Comparative analysis of breast cancer characteristics in young premenopausal and postmenopausal women in Ghana

Breast cancer is increasingly common among young women in Ghana. BCa is heterogeneous with unique traits that impact causes, prognostic, and predictive outcomes of patients before and after menopause. However, limited evidence exists on differences between young premenopausal (YPM) and postmenopausal cases in Ghana. This study compared breast tumour characteristics between YPM women (under 35 years) and postmenopausal women. We conducted a prospective cross-sectional study involving 140 BCa-diagnosed women at the Breast Care Clinic of Komfo Anokye Teaching Hospital (KATH), Kumasi from November 2019 to June 2021. Thirty-one (22.1%) of participants were YPM and 109 (77.9%) were postmenopausal. The median ages for YPM and postmenopausal were 32.0 (range: 25.0–35.0) and 57.0 (48.0–86.0) respectively. Invasive carcinoma was the most common histological type (97.1%). Left tumour location was the most frequent in both groups (51.6% for YPM and 51.8% for postmenopausal). Lumps detected were frequently in the outer upper quadrant in both groups (61.3% and 56.0%). The majority of the YPM women (80.7%) and postmenopausal women (87.0%) had stage III and IV diseases. Most YPM (64.5%) and postmenopausal women (64.4%) exhibited triple-negative breast cancer (TNBC). Both YPM 13 (56.6%) and postmenopausal participants 40 (56.3%) exhibited a predominantly partial response to neo-adjuvant chemotherapy but YPM women (21.7%) experienced disease progression than the postmenopausal women (12.7%). The study highlights consistent tumour characteristics and advanced clinical stages at diagnosis in both groups with a higher prevalence of TNBC. TNBC and HER2+ subtypes respond better to Anthracycline-based neoadjuvant chemotherapy. Establishing Breast Care Clinics in district and regional hospitals for early detection is crucial and further studies are warranted to understand the higher TNBC prevalence in black Africans and re-evaluate breast education programs to address the persistently late presentations.


Study population and subject selection
The study enrolled all young pre-menopausal (YPM) women, defined as women aged 35 years and below and postmenopausal women with a histological confirmed BCa diagnosis presenting at Breast Care Clinic, KATH.The choice of the 35-year age threshold was made by harmonizing the global literature variations of different age cut-offs, such as < 30 years, < 35 years, < 40 years or all pre-menopausal used to define "young" patients with the majority considering under 35 as "young" 11,[17][18][19] .Postmenopausal status was defined as a woman at least 48 years old with 12 consecutive months without menstruation.Patient selection was done using a convenience sampling approach and it took place in the consulting room every day of the week, starting from 8 a.m. to 2 p.m. during the study period.

Data collection and tools
Data collection involved face-to-face interviews using a structured questionnaire with women diagnosed with BCa at the BCC.The questionnaire covered demographics, BCa risk factors, breast examination findings, histological features, and staging investigations.The principal investigator and trained assistant conducted the interviews.The questionnaire was written in English but was carefully translated into the local language to ensure clarity.It was developed with information from literature and guidance from supervising consultants and pretested with 12 BCa patients at the BCC.Problems identified from the pretesting phase were corrected and the final draft was prepared for collection of data.The interviewer administered the questionnaires during the study period.

Inclusion and exclusion criteria
All women in the above age group presenting at the breast clinic with histologically proven diagnoses of breast adenocarcinoma received adriamycin and cyclophosphamide chemotherapeutic agents and consented to the study.Excluded from the study were patients with non-epithelial BCa, individuals with recurrent BCa, those

Statistical analysis
Data was collected using a structured data entry form after which it was entered into Microsoft Excel software.Statistical analyses were performed on R language for statistical computing 28 .The principal variables analysed included immunohistochemistry (intrinsic subtypes,) and tumour characteristics (such as BCa histological type, tumor size, staging investigations, tumour location, site of lump, skin involvement, and type of skin involvement).Additionally, socio-demographic characteristics (age, marital status, educational background, occupational status, and ethnicity) were considered, along with risk factors (menarche, age at full-term pregnancy, family history of BCa, and the use of combined oral contraceptive pills).Menarche was further categorised into early (12 years and below) and late (more than 12 years).Descriptive statistics were used to examine the distribution of the study variables.Data for continuous variables between two groups were presented as means ± standard deviation (SD).Categorical variables were presented as frequencies (n) and percentages (%).Fisher's exact test was performed to test the association of various reproductive and clinicopathological factors with pre and postmenopausal groups.A P-value of less than 0.05 was considered statistically significant.

Sociodemographic characteristics of the study participants
A total of 336 patients received BCa core biopsy diagnoses between November 2019 and June 2021.Of these, 46 (13.7%) were YPM and 165 (49%) were postmenopausal and 125 (38%) were premenopausal aged 36-49 years.Fifteen YPM and 55 of the postmenopausal women did not meet inclusion criteria.Consequently, 141 eligible YPM women recruited for the study.However, the analysis included data from 140 patients, with one patient (0.07%) excluded due to inadequate data.
Table 1 shows the sociodemographic characteristics of the study participants.Among the participants, thirtyone (22.1%) were aged below 35 years, while 109 participants (77.9%) were identified in the post-menopausal phase.The majority of the participants were married (52.9%), engaged in informal occupations (62.2%) attained a basic education level (37.9%), and belonged to the Akan ethnic group.Similar trends in terms of frequencies of the results were observed between those under 35 years and postmenopausal, except for differences in educational category.While 12 (38.7%) of participants under 35 years had received tertiary education, a majority of postmenopausal participants 44 (40.4%) had completed only basic education level.

Association of breast-cancer-related risk factors with postmenopausal status
The majority of the under-35 participants (15, 48.4%) and postmenopausal women (46, 42.24%) experienced full-term pregnancy within 19-29 years.The absence of a family history of BCa was prevalent in both groups, with 27 (87.1%)among those under 35 and 95 (87.2%) among postmenopausal women.Similarly, no usage history of oestrogen-containing contraceptive/hormone replacement therapy was found in both groups: 27 (87.1%)and 100 (91.7%).The majority of the participants under 35 years 15 (48.4%) experienced late menarche, while a majority of post-menopausal participants 53 (48.6%) were unsure.Fisher's exact test revealed no significant correlation between BCa-related risk factors and menopausal status (P > 0.05) (Table 2).

Association of tumour characteristics with postmenopausal women
A greater 107 (98.2%) of the post-menopausal participants had invasive carcinoma.Mean tumour size was significantly higher in those under 35 compared to postmenopausal individuals (8.76 cm ± 6.08 vs. 6.2 cm ± 3.34, P = 0.026).Both groups commonly had Left tumour locations: 51.6% (under 35) and 51.4% (post-menopausal).
The upper outer quadrant was the most prevalent tumour site for both groups: 62% of those under 35 years had upper outer quadrant tumor location with 52% in the post-menopausal group.Tumour-related skin involvement was present in 45.2% of patients under 35, all displaying Peau d' orange.)Fisher's exact test revealed no significant correlation between tumour characteristics and menopausal status (P > 0.05) (Table 3).

Distribution and association of clinical stage and cancer subtype with postmenopausal status
The majority of the under-35 had stage IV cancer 13 (41.9%)and for postmenopausal individuals, it was 50.4%.None of the participants under 35 had stage I BCa.TNBC subtype was the most expressed subtype 20 (64.52%) followed by HER2+ 5 (16.1%) for under-35 participants.Similarly, for post-menopausal participants, TNBC subtype was the most common subtype 70 (64.3%)followed by luminal A 19 (17.4%).There was no statistically significant association between tumour stages (P = 0.456) and tumour subtypes (P = 0.380) with postmenopausal (Fig. 2). ) patients (Fig. 3).

Discussion
BCa accounts for around 16% of all cancer cases in Ghana and is the most common cancer among women 29 .
Early-onset BCa may differ in etiologies, clinical features, and outcomes compared with BCa in older women.
To gain further insight, we prospectively collected and compared demographic, clinico-pathological features, and outcomes of BCa in women under 35 years and those who have reached menopause at a Ghanaian teaching hospital.
The highest incidence of BCa in Ghana is typically observed between the ages of 40 to 49 years.New cases of BCa in women under 35 years at KATH constitute 13% annually as documented in the Breast Cancer Registry book of 2020.In contrast, the United States had considerably lower figures, with less than 3% for women under 35 and 7% for those under 40 30 .Among 336 women diagnosed with BCa during the study, 13.7% were YPM women, 49.1% were postmenopausal, and 37.2% were premenopausal.Similar patterns were observed in a study in Ghana by Clegg-Lamptey et al., showing 8% for YPM, 52% between ages 35-48 years, and 40% above 50 years 21 .Moreover, other regions have reported a higher proportion of BCa cases among women under 35 years, Togo, and Senegal, for instance, have reported 38.3% and 22.6%, respectively 16,17 34 , The disparities may in part be explained by the population age structures and the prevalence of younger populations in African countries.Among young premenopausal in this study, a significant portion were married, and none were divorced or widowed.Among postmenopausal, 49.5% were married, approximately half were either single or divorced, with a small fraction widowed (5%).Similar marital status distributions were reported in an Accra-based study by Iddrisu et    and BCa-related outcomes suggested that younger unmarried BCa women may benefit from additional counseling at the time of diagnosis 36 .While marriage reduces BCa and metastasis risk, it can present psychosocial challenges for young married couples 37,38 .
Reproductive history has been consistently associated with BCa risk 39,40 .Age at menarche, age at first fullterm pregnancy, and nulliparity are well-established risk factors [40][41][42] .However, their specific impact on pre-and postmenopausal BCA risk varies across studies 43 .This study found that the majority of under-35 and postmenopausal women had full-term pregnancies between 19 and 29 years, and many under-35 participants had late menarche.The findings indicated there were no differences in the distribution of reproductive risk factors for BCa in both groups in this study.Both groups also had a high prevalence of no family history of BCa, consistent with reports from the literature, as most BCa patients lack a family history 44 .Experts caution against overemphasizing hereditary factors to avoid false security in some women 45 .
In this study, the commonest pathological type of BCa among YPM and postmenopausal women was invasive carcinoma at 91.67% and 98.17% respectively.These results are consistent with earlier Ghanaian studies which documented comparable findings ranging from 82 to 86% [20][21][22] .Moreover, these findings also mirror reports from a retrospective study by Eiriz et al. 11 where in situ disease accounted for 6.45% of YPM women and 1.03% of postmenopausal women.The average tumor size at diagnosis indicated an advanced-stage disease measuring 8.76 cm (T3) for YPM women and 6.20 cm (T3) for postmenopausal women.Clegg-Lamptey et al. found an average tumour size of 6 × 7 cm in southern Ghana 21 while another study in Tanzania reported an average tumour size of 6 cm 46 .
Most breast cancer lumps for both age groups were located in the upper outer quadrant followed by involvement in multiple quadrants.This result is consistent with reports from previous studies in Ghana [20][21][22] .The increased prevalence in the upper outer quadrant may be attributed to the amount of target epithelial tissue in that region, but other studies have suggested that causative factors may play a role 47 .The study revealed a minimal predilection for the left breast with a left breast/right breast ratio of 1.07 in both groups similar to results from the USA, Europe, and other African countries.Attributable reasons so far are inconclusive 48 .
Both YPM and the postmenopausal group showed concerning rates of advanced stage BCa with 80.65% and 87.1% presented at stages III and IV, respectively.The clinical stage at presentation did not differ between the two groups.Similar trends have been observed in previous studies in Ghana [20][21][22] and many other sub-Saharan African countries 49,50 , indicating a persistent problem of late-stage diagnosis.Efforts to improve breast cancer awareness and education have not led to better early diagnosis rates.Asoogo et al. conducted a study in BCa presenting at KATH and identified key factors contributing to the late presentation including insufficient disease knowledge fear of mastectomy and cancer treatment, poverty, and destructive cultural beliefs 51 .
TNBC is more prominent in premenopausal African American and African women compared to women of European descent 52,53 .In this study, 64.5% of the YPM had TNBC while 16.3% had the HER2 + subtype.Postmenopausal women showed similar proportions 64.2% for TNBC and 11.9% for HER2 subtype and no statistical difference between the two groups.These findings concord with results from a retrospective study done by Mensal et al. in Ghana which high TNBC prevalence (66.38%) and 9.5% for the HER2+ subtype 54 .A comparative study by Jiagge et al. found that in patients under 50 years, TNBC was most prevalent in (50.8%) and African Americans (34.3%) compared with White Americans (16.0%) and Ethiopians (16.0%) 55 .Follow-up populationbased studies supported the link between WA ancestry, increased TNBC rates, and more unfavourable disease outcomes 55 .Additionally, different studies from Nigeria (25.0%) and Kenya (20.3%) have also reported a high prevalence of TNBC 56,57 .Biologic and environmental factors may contribute to racial disparities in TNBC 52 .Tumour grade among young premenopausal women was either 48.39% for grade 2 or 51.61% for grade 3. 96.77% had no lymphovascular invasion.Among postmenopausal patients, tumour grade 2 was 55.96% and grade 3 was 36.70% and 98.17 had no lymphovascular invasion.Similar findings have been reported in different studies in sub-Saharan Africa 56,58 .
In this study, 13.0% of YPM women achieved complete clinical response, with 56.6% showing a partial response, but 21.7% progressed, and 8.7% remained stable.These findings are comparable to reports study by Egwuonwu et al. 59 , where the premenopausal response revealed 12.9% complete clinical response, 61.3% partial response, and 25.8% non-response.In postmenopausal women, 56.3% showed partial response, and 9.9% demonstrated a complete clinical response.However, 12.7% experienced disease progression and 21.1% showed stable disease.These findings highlight the aggressive nature and high progression of BCa in the younger population.Furthermore, among YPM who had either complete or partial response to anthracycline-based neoadjuvant chemotherapy, 80.95% had TNBC or HER2 subtypes, while 19.1% had luminal breast cancer For postmenopausal women with either complete clinical response or partial response, 77.42% had TNBC or HER2+ subtype and 22.6% Luminal A and B These results are consistent with reports from a study done by Carey et al. indicating that Basal-like and HER-molecular subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers 60 .
The study had some limitations, including its single-centre design and small sample size.The reported numbers likely represent gross underestimate of the true prevalence of BCa among YPM and postmenopausal women in Ghana, given that a majority of patients never make it to the hospital for diagnosis.Moreover, the limited sample size undermines the suitability of robust statistical testing.The study did not evaluate loss of androgenreception expression which has been shown to be associated with aggressive BCa in women of African descent, nor did it examine immune markers of exhaustion.Nevertheless, our findings are congruent with previous reports and highlight some significant demographic and clinical characteristics of BCa in YPM and postmenopausal women.

Conclusion
The study highlights consistent tumour characteristics in both YPM and postmenopausal women with a higher prevalence of TNBC in both groups.Advanced clinical stages at diagnosis were common.Anthracycline-based neoadjuvant chemotherapy was effective for TNBC and HER2+ subtypes.YPM women often experience more disease progression.Establishing Breast Care Clinics in district and regional hospitals for early detection is crucial.Further studies are warranted to understand the higher prevalence of TNBC in black Africans and reevaluate breast education programs to address persistently late presentations.

Figure 1 .
Figure 1.Age distribution of below 35 years and postmenopausal participants.
al. for pre-and postmenopausal women with BCa in Ghana 35 .A study by Hinyard et al. marital status

Figure 2 .
Figure 2. Distribution and association of clinical stage and cancer subtype with postmenopausal.

Table 1 .
Socio-demographic characteristics of study groups.BCa: breast cancer.

Table 2 .
Association of breast cancer-related risk factors with post-menopausal status.BCa: breast cancer; AFFTP: age at first-full term pregnancy; ECHRT: oestrogen-containing contraception/hormone replacement therapy.

Table 3 .
. Ntekim et al. found 30.6% of BCa cases in women aged 15 to 39 years in Nigeria 31 while Ntirenganya et al. also reported a proportional rate Association of the tumour characteristics with post-menopausal status.BCa: breast cancer; Interval, LVI: lymphovascular invasion.
Vol.:(0123456789) Scientific Reports | (2024) 14:2704 | https://doi.org/10.1038/s41598-024-52129-w of 45.9% of BCa cases in women below 40 years in Rwanda 32 .The incidence of BCa in YPM women is higher in Africa as compared to other parts of the world.Hwang et al. found 4.4% of women under 35 years in South Korea 33 , Eiriz et al. recorded 2.5% of women under 35 in Portugal 11 , and Jmor et al. reported 2.0% for women under 35 in Edinburg